Eicosanoids are 20-carbon fatty acids (eicosa- means 20) found
in many tissues of the body. These compounds are extremely important
in multiple physiologic responses, such as gastric mucosal protection
and controlling resistance in various vascular beds. They are also
significant mediators of pain and inflammation. Thus, both eicosanoid
agonists and antagonists are important, but the antagonists are
more commonly used clinically.
Inflammation and pain are common manifestations in rheumatic
diseases, and eicosanoid antagonists are heavily prescribed to reduce
symptoms. Other drugs modify the cellular- and humoral-immune responses
in some autoimmune-mediated rheumatic diseases. These drugs are
classified as disease-modifying antirheumatic drugs (DMARDs).
Gout is a disease that results from crystallization of a nucleic
acid metabolite—uric acid, in the body. In the joints,
this crystallization results in inflammation and pain. Patients
with gout are treated with anti-inflammatory drugs, and drugs that
either decrease formation of these metabolites or increase their
excretion. Drug classes discussed in this chapter are reviewed in
Drug classes used in the treatment of inflammation and
associated pain. Anti-inflammatory drugs are divided into nonsteroidal
anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying
antirheumatic drugs (DMARDs). The NSAIDs are further divided based
on their mechanism of action. Acetaminophen is in a drug class alone
because of its mechanism of action. The drugs used in the treatment
of gout are classified as acute or chronic therapies. In the acute phase,
NSAIDs and glucocorticoids are used to decrease inflammation and
associated pain. In the chronic phase, drugs are classified based
on whether they inhibit inflammatory cell function (colchicine),
increase the excretion of uric acid (uricosurics), or inhibit the
formation of uric acid (allopurinol).
The eicosanoids are an important group of endogenous fatty acid
derivatives that are produced from arachidonic acid, a normal constituent
of cell membranes.
Eicosanoids are synthesized in response to a variety of stimuli
(e.g., physical injury, immune reactions). These stimuli activate
phospholipases in the cell membrane or cytoplasm, and arachidonic
acid is released from membrane phospholipids (Figure 34–2).
Arachidonic acid is then metabolized by one of several mechanisms.
Metabolism to straight-chain products is performed by lipoxygenase (LOX), ultimately producing leukotrienes (LTs). Alternatively,
cyclization by the enzyme cyclooxygenase (COX)
results in the production of three major subgroups: prostacyclin (PGI), prostaglandins (PGs), and thromboxane (TX).
There are several series for most of the principal cyclized subgroups
based on different substituents (indicated by letters A, B, etc.)
and different numbers of double bonds (indicated by a subscript
number) in the molecule.
Scheme for mediators of inflammation derived from arachidonic
acid via the cyclooxygenase (COX) or lipoxygenase pathways. Inhibitory
sites of action are presented with dashed arrows. Aspirin and the
nonselective NSAIDs inhibit, ...